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WO1993005045A1 - Imidazolines de benzopyran spirocycliques - Google Patents

Imidazolines de benzopyran spirocycliques Download PDF

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Publication number
WO1993005045A1
WO1993005045A1 PCT/US1992/006291 US9206291W WO9305045A1 WO 1993005045 A1 WO1993005045 A1 WO 1993005045A1 US 9206291 W US9206291 W US 9206291W WO 9305045 A1 WO9305045 A1 WO 9305045A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzopyran
spiro
tetrahydro
formula
imidazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1992/006291
Other languages
English (en)
Inventor
Robert C. Gadwood
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Priority to EP92916735A priority Critical patent/EP0602060A1/fr
Priority to AU24014/92A priority patent/AU655666B2/en
Publication of WO1993005045A1 publication Critical patent/WO1993005045A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is directed toward spirocyclic benzopyran imidazolines of Formula 1, shown below, and their use for treatment of hypertension, alopecia, and erectile dysfunction.
  • the subject compounds act by opening cell membrane potassium channels in similar fashion to o ⁇ erknownagentssuchaspinacidil(N-cyano-N'-(4-pyridyl)-N''-(l > 2,2-trimethylpropyl)guanidine) and cromakalim ((+)-tr ⁇ /w-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-l-yl)-2H-l- benzopyran-3-ol).
  • Pinacidil and its analogues are described by H. J. Petersen, et al in J. Med. Chem., 21, 773-781 (1978) and in US Patent 4,057,636. Cromakalim and its analogues are reported by V. A. Ashwood, et al, in J. Med. Chem. 29, 2194-2201, (1986) and in European Patent EP 76-075 B. Pinacidil and cromakalim are considered as standard potassium channel openers against which new compounds are compared. The compounds of the present invention are surprisingly more active at relaxing vascular smooth muscle than either pinacidil or cromakalim.
  • potassium channel openers have been shown to have relaxant activity in several types of smooth muscle, the compounds of this invention will be useful for treatment of hypertension, asthma, incontinence, premature labor, and erectile dysfunction. In addition, based on results with other potassium channel openers, the compounds of this invention will have activity as hair growth stimulants and will be useful for treatment of alopecia.
  • U.S. Patent 4,874,869 discloses a hydantoin derivative which is useful as an intermediate in the preparation of the subject compounds but does not disclose such preparation or compounds.
  • U.S. Patents 4,874,869 and 4,740,517 disclose hydantoin derivatives and spiro-3- heterozolidine compounds, respectively, which are only cited to show the state of the art.
  • the present invention is a compound of Formula 1 and its pharmaceutically acceptable salts thereof
  • R 1 is H, R 2 , F, Cl, Br, CF 3 , CF 3 0, CN, N0 2 , R 2 S0 2 , R 2 NHS0 2 , R 2 0, R 2 CO, R 2 OCO, or R 2 NHCO;
  • R 2 is linear or branched C 1 -C 10 alkyl, a C 3 -C 8 cycloalkyi, phenyl, or benzyl;
  • R 5 is H or both R 3 together are a double bond to oxygen; and
  • X is S, O, or NH.
  • the subject invention is the use of a compound of Formula 1 in a method for treatment of hypertension by administering an effective amount to a patient suffering from hypertension.
  • the compound of Formula 1 can also be useful in the treatment of male impotence by direct injection or administration of an effective amount to a male suffering from penile dysfunction.
  • the subject invention is directed toward a method for promoting hair growth comprising the topical administration of an effective amount of a compound of Formula 1 or its pharmaceutically acceptable salts.
  • the method comprises the application of an effective amount of Formula 1 to promote hair growth. Typically, amounts range from about 0.01 to about 20, preferably, 0.5 to 5, more preferably 1 to 3 percent by weight of a compound of Formula 1 are applied.
  • the method can also comprise the application of an effective amount of such compound admixed in a pharmaceutical carrier adapted for topical application.
  • the method includes the routine application of such compound to an area of treatment. Further the routine application can comprise a plurality of treatments such as, for example, daily or twice daily to promote hair growth.
  • the present invention is compounds of Formula 1 and pharmaceutically acceptable acid addition salts as structurally depicted above.
  • the compounds of Formula 1 include both enantiomers as well as salts and tautomeric forms.
  • Pharmaceutically acceptable acid addition salts of the Formula 1, may be chosen from the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane- sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methane- sulfon
  • C 1 -C3 alkyl refers to alkyl of 1-3 carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl, and isomeric forms thereof.
  • C -C I Q alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomeric forms thereof (branched and linear).
  • C 3 -Cg cycloalkyi is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and isomeric forms thereof.
  • Preferred compounds of Formula 1 are described below.
  • the compounds of Formula 1 are useful in the treatment of hypertension and as potassium channel openers.
  • the Formula 1 compounds have been shown to have potent hypotensive activity in normotensive rats.
  • these compounds can be administered orally in dosages of from 0.01 mg/kg to 10 mg/kg.
  • the compounds can be administered intravenously, intramuscularly, topically, transdermally such as by skin patches, bucally or orally to man or other animals.
  • the composi ⁇ tions of the present invention can be presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, oil in water and water in oil emulsions containing suitable quantities of the compound, suppositories and in fluid suspensions or solutions.
  • either solid or fluid unit dosage forms can be prepared.
  • the compound can be mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other insert oil.
  • Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared.
  • the forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
  • Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
  • fluid unit dosage forms can be prepared utilizing the compound and a sterile vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • Adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into a vial and the water removed under vacuum.
  • the dry lyophilized powder can then be sealed in the vial and reconstituted prior to use.
  • the compounds of Formula 1 can have utility for treatment of erectile dysfunction (male impotence) via penile injection or via topical penile treatment similar to the known use of prostaglandin.
  • these compounds may be administered via penile injection in quantities of 0.01 to 10.0 mg in an aqueous solution. Alternatively, they may be applied topically to the penis in the same vehicles and concentrations as described for treatment of alopecia.
  • the Formula 1 compounds have utility as hair growth stimulants when applied topically in a suitable vehicle.
  • the Formula 1 compound is applied to mammalian skin in an effective amount whereby hair growth is promoted. Promotion of hair growth is where the growth of hair is induced or stimulated or where the loss of hair is decreased.
  • these compounds can be applied topically to balding areas of the scalp in concentrations from 0.1 to 10% by weight in vehicles such as propylene glycol, ethanol, water, propylene carbonate, or N-methylpyrrolidinone, or combinations of these.
  • Penetration enhancers such as oleyl alcohol in concentrations of 0.1 to 1% by weight may also be employed.
  • the compounds of this invention prepared in examples 7, 8, and 9 are more potent in this assay than cromakalim.
  • the compounds of examples 4, 10, and 16 were more potent than pinacidil.
  • Table 1 The data for relaxation of rabbit mesenteric artery and the comparison with cromakalim and pinacidil are shown below in Table 1.
  • the spirocyclic hydantoins can be prepared by procedures described in detail below which are essentially the same as those described by K. Ueda, et al, in US patent 4,874,869.
  • the compound is prepared by reaction of an alkyl amine such as propyl amine with one of the previously described compounds of formula 1 where X is either O or S.
  • Example 7 Six cynomolgus monkeys were sedated with ketamine. The compound of Example 7 was injected into the corpus cavernosum of each monkey at a dose of 0.75 ⁇ g in 0.1% DMSO/saline solution. Five of the six monkeys showed a positive response which was characterized by penile elevation along with rigidity and pulsation.
  • Example 1 Preparation of 2,3-Dihydro-2,2-dimethyl-spiro-[4H-l-benzopyran-4,4'- imidazolidine]-2',5'-dione (Formula 1', R — H).
  • a glass pressure tube was charged with a mixture of 2,3-dihydro-2,2-dimethyl-4 ⁇ -l- benzopyran- -one (4.4 g, 25 mmol), KCN (5.2 g, 50 mmol) and (NH ⁇ C ⁇ (16.0 g, 187.5 mmol).
  • Enough formamide was added to fill the pressure tube nearly completely (ca. 100 mL). The mixture was heated at 70 °C for 24 h and then at 110 °C for another 48 h.
  • Examplel6 P ⁇ eparation of2,2-Dimethyl-6-fluoro-2'-propylamino-2,3,3',4'-tetrahydro-spiro- [4H-l-benzopvran-4,4'-5'H-imidazorj-5'one.
  • R 1 F
  • R 2 CH 2 CH 2 CH 3
  • X NH

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Composés d'imidazolines de benzopyran spirocycliques de formule (1) dans laquelle R1 représente H, R2, F, Cl, Br, CF¿3?, CF3O, CN, NO2, R?2SO¿2, R2NHSO2, R?2O, R2CO, R2¿OCO, ou R?2NHCO. R2¿ représente un alkyle C¿1?-C10 ramifié ou linéaire, un cycloalkyle, phényle ou benzyle C3-8. X peut représenter S, O, ou NH. Les deux énantiomères font partie de cette invention ainsi que les sels et les formes tautomères de ces composés. Lesdits composés sont utiles dans le traitement de l'hypertension, de l'alopécie et du dysfonctionnement de l'érection.
PCT/US1992/006291 1991-08-28 1992-08-03 Imidazolines de benzopyran spirocycliques Ceased WO1993005045A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92916735A EP0602060A1 (fr) 1991-08-28 1992-08-03 Imidazolines de benzopyranne spirocycliques, leur préparation et leur utilisation comme activateurs des canaux de potassium
AU24014/92A AU655666B2 (en) 1991-08-28 1992-08-03 Spirocyclic benzopyran imidazolines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75059691A 1991-08-28 1991-08-28
US750,596 1991-08-28

Publications (1)

Publication Number Publication Date
WO1993005045A1 true WO1993005045A1 (fr) 1993-03-18

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ID=25018488

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/006291 Ceased WO1993005045A1 (fr) 1991-08-28 1992-08-03 Imidazolines de benzopyran spirocycliques

Country Status (5)

Country Link
US (1) US5430048A (fr)
EP (1) EP0602060A1 (fr)
AU (1) AU655666B2 (fr)
CA (1) CA2113818A1 (fr)
WO (1) WO1993005045A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5464859A (en) * 1993-07-20 1995-11-07 Adir Et Compagnie Benzospiroalkene derivatives
WO2010021680A3 (fr) * 2008-08-19 2010-04-15 Vitae Pharmaceuticals, Inc. Inhibiteurs de la bêta-sécrétase
WO2011072064A1 (fr) * 2009-12-08 2011-06-16 Array Biopharma Inc. Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase
US8633212B2 (en) 2009-03-13 2014-01-21 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8981112B2 (en) 2012-03-05 2015-03-17 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9018391B2 (en) 2012-08-27 2015-04-28 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9909792D0 (en) * 1998-12-04 1999-06-23 Cambridge Bioclinical Limited Potassium channel activators and their use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057932A1 (fr) * 1981-02-11 1982-08-18 E.I. Du Pont De Nemours And Company Dihydro-3,4 (on dihydro-1,4) (1)-benzopyrano(3,4-d)imidazoles portant un groupement thio substitué en position 2 à activité anti-inflammatoire et/ou analgésique et leurs sulfoxydes et sulfones correspondants
EP0193415A2 (fr) * 1985-03-04 1986-09-03 Sanwa Kagaku Kenkyusho Co., Ltd. Composés de spiro-3-hétéroazolidine et leurs sels, leur préparation et agents pharmaceutiques les contenant
EP0344747A1 (fr) * 1988-06-02 1989-12-06 Fujisawa Pharmaceutical Co., Ltd. Dérivés du benzopyranne et procédé pour leur préparation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5745185A (en) * 1980-07-21 1982-03-13 Eisai Co Ltd Hydantoin derivative and its preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057932A1 (fr) * 1981-02-11 1982-08-18 E.I. Du Pont De Nemours And Company Dihydro-3,4 (on dihydro-1,4) (1)-benzopyrano(3,4-d)imidazoles portant un groupement thio substitué en position 2 à activité anti-inflammatoire et/ou analgésique et leurs sulfoxydes et sulfones correspondants
EP0193415A2 (fr) * 1985-03-04 1986-09-03 Sanwa Kagaku Kenkyusho Co., Ltd. Composés de spiro-3-hétéroazolidine et leurs sels, leur préparation et agents pharmaceutiques les contenant
EP0344747A1 (fr) * 1988-06-02 1989-12-06 Fujisawa Pharmaceutical Co., Ltd. Dérivés du benzopyranne et procédé pour leur préparation

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5464859A (en) * 1993-07-20 1995-11-07 Adir Et Compagnie Benzospiroalkene derivatives
WO2010021680A3 (fr) * 2008-08-19 2010-04-15 Vitae Pharmaceuticals, Inc. Inhibiteurs de la bêta-sécrétase
US8450308B2 (en) 2008-08-19 2013-05-28 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9212153B2 (en) 2009-03-13 2015-12-15 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8633212B2 (en) 2009-03-13 2014-01-21 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US10336717B2 (en) 2009-03-13 2019-07-02 Vitae Pharmaceuticals, Llc Inhibitors of beta-secretase
WO2011072064A1 (fr) * 2009-12-08 2011-06-16 Array Biopharma Inc. Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8981112B2 (en) 2012-03-05 2015-03-17 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9526727B2 (en) 2012-03-05 2016-12-27 Vitae Pharmaceutical, Inc. Inhibitors of beta-secretase
US9949975B2 (en) 2012-03-05 2018-04-24 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9018391B2 (en) 2012-08-27 2015-04-28 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase

Also Published As

Publication number Publication date
CA2113818A1 (fr) 1993-03-18
US5430048A (en) 1995-07-04
AU2401492A (en) 1993-04-05
AU655666B2 (en) 1995-01-05
EP0602060A1 (fr) 1994-06-22

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